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Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women's Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.

Background: Although the association of clinical hypothyroidism with cognitive deficits is well known, the cognitive effects of thyroid hormones in euthyroid subjects are less studied and understood. The purpose of this study was to examine thyroid-cognition relationships in healthy, euthyroid older men.Methods: We examined healthy men (N = 44, mean age = 72), excluding clinically hypothyroid/hyperthyroid or diabetic/hyperglycemic subjects and those with dementia, depression, CNS medications, or recent illness. Plasma samples obtained across a 24-hour period were pooled, then assayed for total thyroxine (TT4), total triiodothyronine (TT3), and T3 resin uptake. Free thyroxine index (FT4I) was calculated. A broad cognitive battery (including the Wechsler Adult Intelligence Scale-Revised [WAIS-R], the Dementia Rating Scale [DRS], and the Rivermead Behavioral Profile [PROFILE]) was administered to all subjects.Results: Regression analyses controlling age and education showed TT4 and FT4I to have significant positive relationships with measures of overall cognition; TT4 accounted for 8% to 12% of the variance in omnibus cognitive measures such as WAIS Performance, WAIS Verbal score, and GLOBAL cognitive scores.Conclusions: Our findings suggest that within "normal" range of variation in plasma thyroid hormones, TT4 but not T3 positively associates with general cognition in healthy elderly men. [ABSTRACT FROM AUTHOR]

Importance: Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition., Objective: To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women., Design, Setting, and Participants: Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017., Interventions: Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17β-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month., Main Outcomes and Measures: Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated., Results: The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF., Conclusions and Relevance: Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known., Trial Registration: clinicaltrials.gov Identifier: NCT00154180.

Background: Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women., Methods and Findings: KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y., Conclusions: The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles., Trial Registration: ClinicalTrials.gov NCT00154180 and NCT00623311.

Background: Whether menopausal hormone therapy (MHT) protects against cardiovascular disease (CVD) remains unclear., Objective: To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause., Design: Randomized, controlled trial. (ClinicalTrials.gov: NCT00154180)., Setting: Nine U.S. academic centers., Participants: Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days., Intervention: Oral conjugated equine estrogens (o-CEE), 0.45 mg/d, or transdermal 17β-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months., Measurements: Primary end point was annual change in carotid artery intima-media thickness (CIMT). Secondary end points included changes in markers of CVD risk., Results: Of 727 randomly assigned women, 89.3% had at least 1 follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/y were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment., Limitation: Power to compare clinical events was insufficient., Conclusion: Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk., Primary Funding Source: Aurora Foundation.

Objective: It is unclear why despite a comparable cardiometabolic risk profile, "metabolically benign" overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals., Design and Methods: In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined "metabolically benign" with ≤ 1, and "at-risk" with ≥2 components of the metabolic syndrome., Results: Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62-5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94)., Conclusions: Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state., (Copyright © 2013 The Obesity Society.)

Objectives: While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables., Methods: A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ε4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification., Results: The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were "low-risk" and 38% "high-risk". Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-ε4 was higher in the high-risk class compared with rates in the low-risk class., Conclusion: Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies. ClinicalTrials.gov NCT00154180.

Importance: Growth hormone-releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response., Objective: To examine the neurochemical effects of GHRH in a subset of participants from the parent trial., Design: Randomized, double-blind, placebo-controlled substudy of a larger trial., Setting: Clinical research unit at the University of Washington School of Medicine., Participants: Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study., Interventions: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention., Main Outcomes and Measures: Brain levels of glutamate, inhibitory transmitters γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 × 2 × 2-cm3 left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N-acetylaspartate., Results: After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = -0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects., Conclusions: Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00257712.

Deficiency of growth hormone (GH) in adults results in a syndrome characterized by decreased muscle mass and exercise capacity, increased visceral fat, impaired quality of life, unfavorable alterations in lipid profile and markers of cardiovascular risk, decrease in bone mass and integrity, and increased mortality. When dosed appropriately, GH replacement therapy (GHRT) is well tolerated, with a low incidence of side effects, and improves most of the alterations observed in GH deficiency (GHD); beneficial effects on mortality, cardiovascular events, and fracture rates, however, remain to be conclusively demonstrated. The potential of GH to act as a mitogen has resulted in concern over the possibility of increased de novo tumors or recurrence of pre-existing malignancies in individuals treated with GH. Though studies of adults who received GHRT in childhood have produced conflicting reports in this regard, long-term surveillance of adult GHRT has not demonstrated increased cancer risk or mortality.

Background: Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes., Objectives: This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317., Design: This was a randomized, double-blind, placebo-controlled, single ascending dose study., Patients: Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo)., Setting: The study was conducted in 17 adult endocrinology centers in North America and Europe., Main Outcome Measures: Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed., Results: At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3-5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed., Conclusions: The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.

Context: In the absence of panhypopituitarism and low serum IGF-I levels, the diagnosis of adult GH deficiency (AGHD) requires confirmation with a GH stimulation test. Macimorelin is a novel, orally active ghrelin mimetic that stimulates GH secretion., Objective: The objective of the study was to determine the diagnostic efficacy and safety of macimorelin in AGHD., Design: This was a multicenter open-label study comparing the diagnostic accuracy of oral macimorelin with that of arginine+GHRH in AGHD patients and healthy, matched controls. After 43 AGHD patients and 10 controls were tested, the GHRH analog Geref Diagnostic [GHRH(1-29)NH2] became unavailable in the United States. The study was completed by testing 10 additional AGHD patients and 38 controls with macimorelin alone., Main Outcome Measure: Peak GH area under the receiver operating characteristic curve after macimorelin was measured., Results: Fifty AGHD subjects and 48 controls were evaluated. Peak GH levels in AGHD patients and controls after macimorelin were 2.36 ± 5.69 and 17.71 ± 19.11 ng/mL, respectively (P < .0001). With macimorelin, the receiver operating characteristic analysis yielded an optimal GH cut point of 2.7 ng/mL, with 82% sensitivity, 92% specificity, and 13% misclassification rate. For subjects receiving both tests, macimorelin showed discrimination comparable with arginine+GHRH (area under the receiver operating characteristic curve 0.99 vs 0.94, respectively, P = .29). Obesity (body mass index > 30 kg/m(2)) was present in 58% of subjects, and peak GH levels were inversely associated with body mass index in controls (r = -0.37, P = .01). Using the separate cut points of 6.8 ng/mL for nonobese and 2.7 for obese subjects reduced the misclassification rate to 11%. Only 1 drug-related serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported., Conclusion: Oral macimorelin is safe, convenient, and effective in diagnosing AGHD with accuracy comparable with the arginine+GHRH test.

The availability of synthetic recombinant human growth hormone (GH) in potentially unlimited quantities since the 1980s has improved understanding of the many nonstatural effects of GH on metabolism, body composition, physical and psychological function, as well as the consequences of GH deficiency in adult life. Adult GH deficiency is now recognized as a distinct if nonspecific syndrome with considerable adverse health consequences. GH replacement therapy in lower doses than those used in children can reverse many of these abnormalities and restore functional capacities toward or even to normal; if dosed appropriately, GH therapy has few adverse effects. Although some doubts remain about possible long-term risks of childhood GH therapy, most registries of adult GH replacement therapy, albeit limited in study size and duration, have not shown an increased incidence of cancers or of cardiovascular morbidity or mortality.

Objective: To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis., Design: Cross-sectional analysis., Setting: Multicenter, randomized controlled trial., Patient(s): Recently menopausal women (n = 868) screened for the Kronos Early Estrogen Prevention Study (KEEPS)., Intervention(s): None., Main Outcome Measure(s): Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum E2 levels, and measures of atherosclerosis were assessed. Atherosclerosis was quantified using coronary artery calcium (CAC) Agatston scores (n = 771) and carotid intima-media thickness (CIMT). Logistic regression model of menopausal symptoms and E2 was used to predict CAC. Linear regression model of menopausal symptoms and E2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, E2, CAC, and CIMT were assessed., Result(s): In early menopausal women screened for KEEPS, neither E2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations and depression approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness, and E2., Conclusion(s): Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine whether baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease., Clinical Trial Registration Number: NCT00154180., (Published by Elsevier Inc.)

Background: Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI)., Objective: To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI., Design: Randomized,double-blind,placebo-controlled trial., Setting: Clinical Research Center, University of Washington School of Medicine in Seattle., Participants: A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study., Intervention: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc),a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout(week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition., Main Outcome Measures: Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference,Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test,and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample., Results: The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults.The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory(P=.08). Treatment with GHRH increased insulin like growth factor 1 levels by 117 %(P.001), which remained within the physiological range, and reduced percent body fat by 7.4%(P.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35%in adults with MCI (P.001) but not in healthy adults. Adverse events were mild and were reported by 68%of GHRH treated adults and 36% of those who received placebo., Conclusions: Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.”, Trial Registration: clinicaltrials.gov Identifier: NCT00257712

Purpose of Review: This article summarizes recent advances in testing for growth hormone deficiency (GHD) in adults, focusing on critical appraisal of existing growth hormone (GH) provocative tests as well as newer tests in development., Recent Findings: The diagnosis of GHD can be challenging and often requires the use of GH provocative testing. The most widely validated of these is insulin-induced hypoglycemia (ITT), which requires close supervision and has significant contraindications and side-effects. The arginine-growth hormone-releasing hormone (GHRH) test had become widely used as a safe and accurate alternative to the ITT, but GHRH is currently unavailable for clinical use in the USA. On the basis of review of recent literature we recommend that in the absence of GHRH, glucagon stimulation testing should be the preferred alternative to ITT. Several synthetic GH secretagogues that mimic the gastric peptide ghrelin are currently in development and may become available for use in the diagnosis of GHD in the near future. Other GH provocative tests suitable for use in children lack adequate specificity for the diagnosis of GHD in adults., Summary: Due to the current unavailability of the arginine-GHRH test in the USA, when ITT is contraindicated or impractical we recommend the glucagon stimulation testing as the GH provocative test of choice. There remains a need for a simple, safe and accurate test for the diagnosis of GHD.

Background: The published literature regarding the relationships between retinol-binding protein 4 (RBP4) and cardiometabolic risk factors and subclinical atherosclerosis is conflicting, likely due, in part, to limitations of frequently used RBP4 assays. Prior large studies have not utilized the gold-standard western blot analysis of RBP4 levels., Methods: Full-length serum RBP4 levels were measured by western blot in 709 postmenopausal women screened for the Kronos Early Estrogen Prevention Study. Cross-sectional analyses related RBP4 levels to cardiometabolic risk factors, carotid artery intima-media thickness (CIMT), and coronary artery calcification (CAC)., Results: The mean age of women was 52.9 (± 2.6) years, and the median RBP4 level was 49.0 (interquartile range 36.9-61.5) μg/mL. Higher RBP4 levels were weakly associated with higher triglycerides (age, race, and smoking-adjusted partial Spearman correlation coefficient = 0.10; P = 0.01), but were unrelated to blood pressure, cholesterol, C-reactive protein, glucose, insulin, and CIMT levels (all partial Spearman correlation coefficients ≤0.06, P > 0.05). Results suggested a curvilinear association between RBP4 levels and CAC, with women in the bottom and upper quartiles of RBP4 having higher odds of CAC (odds ratio [95% confidence interval] 2.10 [1.07-4.09], 2.00 [1.02-3.92], 1.64 [0.82-3.27] for the 1st, 3rd, and 4th RBP4 quartiles vs. the 2nd quartile). However, a squared RBP4 term in regression modeling was non-significant (P = 0.10)., Conclusions: In these healthy, recently postmenopausal women, higher RBP4 levels were weakly associated with elevations in triglycerides and with CAC, but not with other risk factors or CIMT. These data using the gold standard of RBP4 methodology only weakly support the possibility that perturbations in RBP4 homeostasis may be an additional risk factor for subclinical coronary atherosclerosis., Trial Registration: ClinicalTrials.gov number NCT00154180.

Estradiol has potent favorable effects on brain function and behavior in animals while in human trials, the results are inconsistent. A number of potential mediating variables influencing response to estradiol have been proposed to account for this variability, 1 of which includes stress. We conducted a placebo-controlled study to examine joint and independent effects of estradiol and elevated levels of the stress hormone cortisol on cognition and biomarkers of aging and neurodegenerative disease. Thirty-nine healthy postmenopausal women (56-84 years) received 0.10 mg/dL of transdermal 17β-estradiol (E2) or placebo for 8 weeks. During the last 4 days of the trial, subjects also received 90 mg/day (30 mg 3×/day) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The 4 groups thus included placebo (placebo patch/placebo pill), CORT-alone (placebo patch/hydrocortisone), E2-alone (estradiol patch/placebo pill), and E2+CORT (estradiol patch/hydrocortisone). Eight weeks of E2 increased plasma estradiol by 167%, and 4 days of CORT increased plasma cortisol by 119%. Overall, E2 had favorable effects on verbal memory (p = 0.03), working memory (p = 0.02), and selective attention (p = 0.04), and the magnitude of these effects was attenuated for E2+CORT. E2-alone and E2+CORT had opposing effects on plasma levels of the amyloid-β (Aβ) biomarker (Aβ40/42 ratio, p < 0.05), with the more favorable response observed for E2-alone. CORT-induced increases in insulin-like growth factor-1 were blunted by E2 coadministration. Our findings indicate that cognitive and physiological responses to estradiol are adversely affected by elevated stress hormone levels of cortisol in healthy postmenopausal women., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women., Methods: Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n=650)., Results: Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r=0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides=-0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; p for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat., Conclusion: While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006., Consensus Process: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes., Conclusions: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

Largely on the basis of the first publication of findings of net harm with menopausal hormone treatment in the Women's Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the "…shortest duration consistent with treatment goals…," with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the "timing hypothesis"). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary heart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1.08 (95% confidence interval, 0.86-1.36) in years 1 to 6 and as 0.46 (confidence interval, 0.28-0.78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk:benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Context: GH secretion declines with age, possibly contributing to reduced muscle mass, strength, and function. GH secretagogues (GHS) may increase muscle mass and physical performance., Objectives/design: We conducted a randomized, double-masked, placebo-controlled, multicenter study to investigate the hormonal, body composition, and physical performance effects and the safety of the orally active GHS capromorelin in older adults with mild functional limitation. INTERVENTION/PARTICIPANTS: A total of 395 men and women aged 65-84 yr were randomized for an intended 2 yr of treatment to four dosing groups (10 mg three times/week, 3 mg twice a day, 10 mg each night, and 10 mg twice a day) or placebo. Although the study was terminated early according to predetermined treatment effect criteria, 315 subjects completed 6 months of treatment, and 284 completed 12 months., Results: A sustained dose-related rise in IGF-I concentrations occurred in all active treatment groups. Each capromorelin dose prompted a rise in peak nocturnal GH, which was greatest with the least frequent dosing. At 6 months, body weight increased 1.4 kg in subjects receiving capromorelin and decreased 0.2 kg in those receiving placebo (P = 0.006). Lean body mass increased 1.4 vs. 0.3 kg (P = 0.001), and tandem walk improved by 0.9 sec (P = 0.02) in the pooled treatment vs. placebo groups. By 12 months, stair climb also improved (P = 0.04). Adverse events included fatigue, insomnia, and small increases in fasting glucose, glycosylated hemoglobin, and indices of insulin resistance., Conclusions: In healthy older adults at risk for functional decline, administration of the oral GHS capromorelin may improve body composition and physical function.

Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimer's disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD = 7, amnestic mild cognitive impairment = 9; apolipoprotein E [APOE] epsilon4- [no epsilon4 alleles] = 9, epsilon4+ [1-2 epsilon4 alleles] = 7), and 19 cognitively-intact older adults (APOE epsilon4- = 17, epsilon4+ = 1). On separate days, fasting participants received counterbalanced infusions of: 1) insulin (1 mU.kg(-1).min(-1)) and dextrose to maintain euglycemia; 2) octreotide (150 microg/h); 3) insulin, dextrose, and octreotide; or 4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for epsilon4- patients, relative to epsilon4+ patients (P = 0.0012). Furthermore, epsilon4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P = 0.0298). For healthy adults, octreotide facilitated memory (P = 0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P = 0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE epsilon4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia.

Observational studies show that women who take menopausal hormone therapy (MHT) have a greatly reduced risk of coronary heart disease (CHD). But in some large randomized controlled trials, MHT failed to decrease CHD and so has been deemed inappropriate for long-term prophylaxis against atherosclerosis or other chronic diseases associated with the menopause. Despite the apparent strength of this conclusion, several recent reports suggest that MHT could be atheroprotective when started close to the menopause, and effects of early discontinuation of MHT have never been studied in randomized trials. Here, we examine these reports and highlight existing uncertainty regarding the effects of long-term continuation versus early discontinuation of early-start MHT on atherosclerosis and CHD risk. We call for new research on this question, and an evidence-based review of existing recommendations for MHT.

Although growth hormone (GH) is primarily associated with linear growth in childhood, it continues to have important metabolic functions in adult life. Adult GH deficiency (AGHD) is a distinct clinical entity, and GH replacement in AGHD can improve body composition, strength, aerobic capacity, and mood, and may reduce vascular disease risk. While there are some hormone-related side effects, the balance of benefits and risks is generally favorable, and several countries have approved GH for clinical use in AGHD. GH secretion declines progressively and markedly with aging, and many age-related changes resemble those of partial AGHD. This suggests that replacing GH, or stimulating GH with GH-releasing hormone or a GH secretagogue could confer benefits in normal aging similar to those observed in AGHD--in particular, could reduce the loss of muscle mass, strength, and exercise capacity leading to frailty, thereby prolonging the ability to live independently. However, while most GH studies have shown body composition effects similar to those in AGHD, functional changes have been much less inconsistent, and older adults are more sensitive to GH side effects. Preliminary reports of improved cognition are encouraging, but the overall balance of benefits and risks of GH supplementation in normal aging remains uncertain.

Context: Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD)., Objective: The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen., Design: This was a randomized, two-arm, parallel, open-label study., Setting: The study was conducted at five academic medical centers with exercise physiology laboratories., Subjects: Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease., Interventions: The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk., Main Outcome Measures: Maximal oxygen consumption (VO2 max) and oxygen consumption (VO2) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured., Results: In the group as a whole, VO2 max increased significantly (by 9%) from baseline (19.1+/- 0.89 ml/kg.min) to end point (21.6 +/- 1.23 ml/kg.min, P = 0.010). Compared with baseline, VO2 max also changed significantly within the individualized dose titration regimen group (+2.5 +/- 0.98 ml/kg.min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 +/- 0.78 ml/kg.min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO2 at lactate threshold, VO2 at ventilatory threshold, and weekly energy expenditure also did not change., Conclusions: GH replacement therapy in GH-deficient adults improved VO2 max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.

Objective: The objective is to provide guidelines for the evaluation and treatment of adults with GH deficiency (GHD)., Participants: The chair of the Task Force was selected by the Clinical Guidelines Subcommittee of The Endocrine Society (TES). The chair selected five other endocrinologists and a medical writer, who were approved by the Council. One closed meeting of the group was held. There was no corporate funding, and members of the group received no remuneration., Evidence: Only fully published, peer-reviewed literature was reviewed. The Grades of Evidence used are outlined in the Appendix., Consensus Process: Consensus was achieved through one group meeting and e-mailing of drafts that were written by the group with grammatical/style help from the medical writer. Drafts were reviewed successively by the Clinical Guidelines Subcommittee, the Clinical Affairs Committee, and TES Council, and a version was placed on the TES web site for comments. At each level, the writing group incorporated needed changes., Conclusions: GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks of GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

Declines in the activity of the somatotrophic axis have been implicated in the age-related changes observed in a number of physiological functions, including cognition. Such age-related changes may be arrested or partially reversed by hormonal supplementation. We examined the effect of 6 months treatment with daily growth hormone releasing hormone (GHRH) or placebo on the cognition of a group of 89 healthy older (68.0+/-0.7) adults. GHRH resulted in improved performance on WAIS-R performance IQ (p<0.01), WAIS-R picture arrangement (p<0.01), finding A's (p<0.01), verbal sets (p<0.01) and single-dual task (p<0.04). GHRH-based improvements were independent of gender, estrogen status or baseline cognitive capacity. These results demonstrate that the age-related decline in the somatotrophic axis may be related to age-related decline in cognition. Further they indicate that supplementation of this neuro-hormonal axis may partially ameliorate such cognitive declines in healthy normal older adults and potentially in individuals with impaired cognitive function (i.e., mild cognitive impairment and Alzheimer's disease).

Only approximately 20% of adults with GH deficiency (GHD) have a history of childhood-onset GHD; the remainder acquire GHD in adult life, usually through acquired damage to the pituitary-hypothalamic region. Diagnosis of GHD in adults is more difficult than in children and is made first from the clinical context, reinforced by signs and symptoms, and then confirmed by biochemical testing. The signs and symptoms, however, including altered body composition, reduced energy, and mild depression, are too common to have diagnostic value without a suggestive clinical context. Furthermore, biochemical tests for GH or IGF-I levels are imperfect, characterized by significant false-positive and -negative rates. GH dosing in adults has shifted to an individualized dose-titration approach, in which treatment is begun at a fixed dose and then titrated upward until IGF-I levels normalize, significant side effects develop, or beneficial effects plateau. Generally, women require higher GH doses than do men. Reflecting age-related differences in normal GH secretion, GH doses may be higher in young adults and lower in older patients.

Extended Antarctic residence (AR) is associated with an increase in serum TSH, a decrease in free T(4), and an increase in T(3) production and clearance. It is not clear whether these adaptations reflect changes in clearance alone or whether intrinsic thyroidal synthetic activity also changes. Thyroglobulin (Tg) secretion is an independent marker of intrinsic thyroid activity whose kinetics are independent of those of T(3) and T(4). In this study we examined changes in Tg levels in healthy subjects before and during AR and their responses to thyroid supplementation to help determine whether alterations in thyroid activity, and not just kinetics of clearance, underlie the changes seen with the polar T(3) syndrome. In cohort 1, we compared measurements of TSH and Tg in 12 subjects before deployment and monthly for 11 months during AR. In cohort 2, we compared the same measurements in 12 subjects monthly for 11 months of AR. Subjects were randomized to receive either placebo or levothyroxine in cohort 1 for 7 months and in cohort 2 for 11 months. Tg increased over baseline during the first 4 months of AR by 17.0 +/- 4.6% and after 7 more months by 31.7 +/- 4.3% over baseline in the placebo group of both cohorts (P < 0.0002). When L-T(4) was taken, Tg returned to a value not different from baseline (4.5 +/- 3.9%). The percent changes from baseline in serum TSH and Tg during AR were highly correlated (P < 0.00003) in the placebo group for both cohorts. The rise in Tg with TSH and the reduction in Tg with L-T(4) provide evidence of target tissue response to TSH and further confirm the TSH rise as physiologically significant. The results also suggest that the adaptive changes in thyroid hormone economy with AR reflect TSH-dependent changes in thyroid synthetic activity, which may help explain a portion of the increases in T(3) production found with AR.

Growth hormone (GH) secretion declines with aging, and parallels between normal aging and the signs and symptoms of adult GH deficiency have led to interest in the potential utility of replacing or stimulating GH to promote physical and psychological function and to prolong the capacity for independent living in older adults. The aging pituitary remains responsive to GH-releasing hormone (GHRH) and to ghrelin-mimetic GH secretagogues (GHS), and these agents have both theoretical and practical potential advantages as alternatives to the use of GH itself in this setting. Studies of the long duration and large scale needed to test the efficacy of GHRH or GHS on clinically important endpoints cannot be designed or conducted without first obtaining promising results in studies of smaller size focused on manageable intermediate endpoints, and all studies published to date have been of this latter type. GHRH and GHS both stimulate GH secretion, and, when given repeatedly, elevate IGF-I levels to within younger adult normal ranges. When GHRH treatment is continued for several months, these hormonal changes yield an increase in lean body (muscle) mass. GHRH, like GH, reduces body fat, but similar effects have not yet been shown with GHS. GHRH treatment has not yielded consistent improvements in physical function, although it may have a stabilizing effect. Chronic treatment with a short-acting GHRH did not improve sleep, possibly due to lack of sustained activity throughout the night. Compared to placebo, GHRH treatment improved certain tests of cognitive performance. These results, while encouraging, do not yet support the routine use of GHRH or GHS in normal aging.

GHRP-2 (GPA-748, Wyeth-Ayerst) is an orally active peptide growth hormone (GH) secretagogue which acts through a G-protein coupled receptor for which the natural ligand--an acylated 28 amino acid peptide, ghrelin--was recently isolated. Ghrelin and its analogs have potent GH-releasing activities, but in animal studies ghrelin also causes weight gain. As part of a study examining the effect of GHRP-2 on GH secretory dynamics and growth, we evaluated its effects on appetite and body weight. Ten prepubertal children with GH deficiency (growth velocity < or = 4 cm/year in association with a GH response to two provocative stimuli < 10 ng/ml) were included in the study. At the beginning of the study their age was 10.4 +/- 2 years (mean +/- SD), with a height of -3.8 +/- 0.1 SDS. Body mass index (BMI) was 17.9 +/- 3.6 kg/m2, and the BMI Z score 0.21 +/- 1.51 SDS. GHRP-2 was administered orally at a dose of 900 microg/kg b.i.d. for 12 months. Seven out of ten patients reported a significant increase in appetite during the first 6 months of the study. There was a tendency for the BMI SDS to increase during the study, but this increase did not reach statistical significance (0.21 +/- 1.5 vs 0.25 +/- 1.5 SDS). These results suggest that at a dose of 900 microg/kg b.i.d., GHRP-2 appears to have a transient stimulatory effect on appetite, but does not have a chronic clinically significant effect on BMI in children with GH deficiency.

Growth hormone (GH) is classically linked with linear growth in childhood but continues to have important metabolic actions throughout life. GH deficiency in adulthood causes a distinct syndrome with significant morbidities. These include increased total and visceral fat, decreased muscle mass and aerobic capacity, affective disturbances, abnormal lipids, and increased vascular mortality, all of which are ameliorated with GH replacement. The possibility of adult GH deficiency (AGHD) should always be considered in individuals with a history of childhood GH deficiency or significant hypothalamic-pituitary damage, and the diagnosis should then be confirmed by biochemical testing. Adult GH dosing is much lower than that in pediatric practice, as appropriate for physiologic reconstitution. Hormonal side effects are minimized by stepwise dose titration. Lingering concerns remain regarding the possibility of increased cancer risk with long-term treatment, but this hazard has not been unequivocally demonstrated. Compared with AGHD, there is much less information about GH replacement in other diseases or in normal aging, or about the use of supraphysiologic GH doses to treat catabolic states. In critical illness, high-dose GH therapy has proven clearly harmful, and the balance of risks and benefits of GH administration in most adult contexts other than AGHD has not been defined.

Aging is accompanied by gradual but progressive reductions in the secretion of testosterone and growth hormone in men, and by alterations in body composition and functional capacity that, to some degree, undo the effects of puberty. Preventing or reversing these changes with the use of trophic factors, including androgens, growth hormone, and growth hormone secretagogues, is an appealing prospect, but documenting the effectiveness of these interventions and their benefits and risks has proven to be a difficult undertaking that is far from complete. Small-scale clinical studies have shown that it is practicable to boost growth hormone and IGF-1 levels for periods of up to 12 months, and testosterone for up to 36 months, to reverse at least some age-related changes in body composition. Information regarding the effects of these interventions on strength, exercise capacity, and the ability to perform activities of daily living is still sparse, and additional reports from recently completed or currently ongoing clinical trials will not provide sufficient data to make firm conclusions. From the limited information currently available, androgen supplementation may be of benefit in some men aged more than 65 years, particularly in men with low serum testosterone levels (< 2 ng/mL). In this group, supplemental androgen therapy would be expected to increase lean body mass, bone mass, and possibly strength. In older men with testosterone levels between 2 and 3.5 ng/mL, some benefit might result from androgen supplementation, but it is not yet clear whether the benefits outweigh the risks. For men in this category, one might consider a 6- to 12-month trial of therapy after a full discussion and explicit consent, followed by a reassessment of the value of ongoing treatment. The even more limited data on growth hormone or growth hormone secretagogue interventions in aging do not support their general clinical use in healthy older men. Growth hormone is much more expensive than testosterone and is not covered by insurance for off-label uses. Patients who persistently seek a trial of therapy should be encouraged to enroll in a study if one is locally available. All of the growth hormone studies reported to date have focused, generally for reasons of safety, on healthy and robust groups of older subjects, men in whom the need for intervention is least compelling and in whom the functional effects of treatment may be the most difficult to observe. Phase II studies of intermediate size and duration examining prefrail groups of elderly who are at greater risk for functional loss and who stand to benefit the most from either preventive or restorative interventions are underway but are limited to the intermediate outcomes of body composition, strength, and function. Trials designed to assess clinically relevant final outcomes, such as falls, fractures, and institutionalization, are of necessity large-scale, long-term, and expensive. Support for larger phase III studies of growth hormone is unlikely to be forthcoming until the phase II studies are completed and show further promise. A multicenter clinical trial of testosterone is currently being planned under the joint sponsorship of the National Institute on Aging, the Veterans Health Administration, and industry, aimed at assessing the effects of testosterone on the risk for falls and fractures. The results of this trial and other large clinical trials should help to better define the balance of benefits and risks of trophic factor intervention in normal older men.

Many of the body's systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline. Significant sleep disturbances are associated with increases in morbidity and mortality. Cognition declines, impacting an older individual's ability to function independently. Interventions that could at least stabilize or possibly improve functional capacity, sleep quality, and cognitive function have the theoretical potential to prolong an older individual's ability to live independently, and interest in their possible utility is growing rapidly. One such intervention may be stimulation of the "somatotrophic" axis via growth hormone-releasing hormone (GHRH). Here we review the evidence for such somatotrophic interventions. We also report preliminary findings on the effects of chronic GHRH treatment on the somatotrophic hormones, body composition, functional status, sleep, and cognitive function of healthy older men and women from two major GHRH intervention studies, one recently completed and the other ongoing.